PMID- 27610652
OWN - NLM
STAT- MEDLINE
DCOM- 20170719
LR  - 20180507
IS  - 1945-7197 (Electronic)
IS  - 0021-972X (Linking)
VI  - 101
IP  - 12
DP  - 2016 Dec
TI  - Hypoxia-Dependent HIF-1 Activation Impacts on Tissue Remodeling in Graves' 
      Ophthalmopathy-Implications for Smoking.
PG  - 4834-4842
AB  - CONTEXT: In Graves' ophthalmopathy (GO), inflammation with tissue expansion in a 
      closed compartment like the bony orbit and smoking may cause tissue hypoxia. 
      OBJECTIVES: In this study, we investigated whether hypoxia-inducible factor-1 
      (HIF-1) action impacts on tissue remodeling in GO with the aim to identify 
      possible new therapeutic targets. DESIGN/SETTING/PARTICIPANTS: Orbital 
      fibroblasts (OFs) were derived from GO patients and control (Ctrl) persons. We 
      analyzed HIF-1alpha levels in response to hypoxia and cigarette smoke extract, as 
      well as HIF-1-dependent vascular endothelial growth factor (VEGF) release and 
      adipogenic differentiation, by using HIF-1alpha small interfering RNA, or HIF-1 
      inhibitor BAY 87-2243. MAIN OUTCOME MEASURES: Western blot, real-time PCR, ELISA, 
      and immunohistochemistry were used to analyze HIF-1alpha, VEGF, CD31, and 
      adiponectin. Adipogenic differentiation was measured with Nile red assay. 
      RESULTS: Higher HIF-1alpha levels in OFs were correlated with the clinical activity 
      score of GO patients. Cigarette smoke extract elevated HIF-1alpha levels. 
      HIF-1-dependent VEGF secretion was enhanced in GO-OF compared to Ctrl-OF, and as 
      an in vivo consequence, we found a higher vessel density in GO tissue than in 
      Ctrl tissue. Hypoxia strongly stimulated HIF-1-dependent adipogenesis and 
      adiponectin release of GO-OF and enhanced TSH receptor-mediated adipogenesis. 
      CONCLUSIONS: Hypoxia impacts on tissue remodeling in GO by stimulating 
      angiogenesis and adipogenesis through activation of HIF-1-dependent pathways in 
      OFs. Our results offer a molecular mechanism for the detrimental influence of 
      smoking on GO and an explanation as to why decompression can improve the outcome 
      of patients. Drug-targeted inhibition of HIF-1/VEGF may provide a therapeutic 
      option to control tissue expansion in GO.
FAU - Gortz, Gina-Eva
AU  - Gortz GE
AD  - Molecular Ophthalmology (G.-E.G., M.H., B.A., A.E., U.B.-P.), Department of 
      Ophthalmology, University of Duisburg-Essen, 45147 Essen, Germany; and Institute 
      of Physiology (B.D.R., J.F.), University of Duisburg-Essen, 45147 Essen, Germany.
FAU - Horstmann, Mareike
AU  - Horstmann M
AD  - Molecular Ophthalmology (G.-E.G., M.H., B.A., A.E., U.B.-P.), Department of 
      Ophthalmology, University of Duisburg-Essen, 45147 Essen, Germany; and Institute 
      of Physiology (B.D.R., J.F.), University of Duisburg-Essen, 45147 Essen, Germany.
FAU - Aniol, Barbara
AU  - Aniol B
AD  - Molecular Ophthalmology (G.-E.G., M.H., B.A., A.E., U.B.-P.), Department of 
      Ophthalmology, University of Duisburg-Essen, 45147 Essen, Germany; and Institute 
      of Physiology (B.D.R., J.F.), University of Duisburg-Essen, 45147 Essen, Germany.
FAU - Reyes, Buena Delos
AU  - Reyes BD
AD  - Molecular Ophthalmology (G.-E.G., M.H., B.A., A.E., U.B.-P.), Department of 
      Ophthalmology, University of Duisburg-Essen, 45147 Essen, Germany; and Institute 
      of Physiology (B.D.R., J.F.), University of Duisburg-Essen, 45147 Essen, Germany.
FAU - Fandrey, Joachim
AU  - Fandrey J
AD  - Molecular Ophthalmology (G.-E.G., M.H., B.A., A.E., U.B.-P.), Department of 
      Ophthalmology, University of Duisburg-Essen, 45147 Essen, Germany; and Institute 
      of Physiology (B.D.R., J.F.), University of Duisburg-Essen, 45147 Essen, Germany.
FAU - Eckstein, Anja
AU  - Eckstein A
AD  - Molecular Ophthalmology (G.-E.G., M.H., B.A., A.E., U.B.-P.), Department of 
      Ophthalmology, University of Duisburg-Essen, 45147 Essen, Germany; and Institute 
      of Physiology (B.D.R., J.F.), University of Duisburg-Essen, 45147 Essen, Germany.
FAU - Berchner-Pfannschmidt, Utta
AU  - Berchner-Pfannschmidt U
AD  - Molecular Ophthalmology (G.-E.G., M.H., B.A., A.E., U.B.-P.), Department of 
      Ophthalmology, University of Duisburg-Essen, 45147 Essen, Germany; and Institute 
      of Physiology (B.D.R., J.F.), University of Duisburg-Essen, 45147 Essen, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160909
PL  - United States
TA  - J Clin Endocrinol Metab
JT  - The Journal of clinical endocrinology and metabolism
JID - 0375362
RN  - 0 
      (1-cyclopropyl-4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-yl)piperazine)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Oxadiazoles)
RN  - 0 (Pyrazoles)
RN  - 0 (Vascular Endothelial Growth Factor A)
SB  - IM
MH  - Adipogenesis
MH  - Cell Culture Techniques
MH  - Fibroblasts/metabolism
MH  - Graves Ophthalmopathy/*metabolism/*pathology
MH  - Humans
MH  - Hypoxia/*metabolism/pathology
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors/*metabolism
MH  - Neovascularization, Pathologic/metabolism
MH  - Orbit/cytology
MH  - Oxadiazoles/pharmacology
MH  - Pyrazoles/pharmacology
MH  - Smoking/*metabolism
MH  - Vascular Endothelial Growth Factor A/*metabolism
EDAT- 2016/09/10 06:00
MHDA- 2017/07/20 06:00
CRDT- 2016/09/10 06:00
PHST- 2016/09/10 06:00 [pubmed]
PHST- 2017/07/20 06:00 [medline]
PHST- 2016/09/10 06:00 [entrez]
AID - 10.1210/jc.2016-1279 [doi]
PST - ppublish
SO  - J Clin Endocrinol Metab. 2016 Dec;101(12):4834-4842. doi: 10.1210/jc.2016-1279. 
      Epub 2016 Sep 9.